Pleural Uptake Patterns in F18Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) Scans Improve the Identification of Malignant Pleural Effusions.

BACKGROUND: The confirmation of malignant pleural effusions (MPE) requires an invasive procedure. Diagnosis can be difficult and may require repeated thoracentesis or biopsies. F18Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) can characterize the extent of malignant involvement in areas of increased uptake. Patterns of uptake in the pleura may be sufficient to obviate the need for further invasive procedures. METHODS: This is a retrospective review of patients with confirmed malignancy and suspected MPE. Patients who underwent diagnostic thoracentesis with cytology and contemporaneous FDG-PET were identified for analysis. Some underwent confirmatory pleural biopsy. The uptake pattern on FDG-PET underwent blinded review and was categorized based on the pattern of uptake. RESULTS: One hundred consecutive patients with confirmed malignancy, suspected MPE and corresponding FDG-PET scans were reviewed. MPE was confirmed in 70 patients with positive pleural fluid cytology or tissue pathology. Of the remaining patients, 15 had negative cytopathology, 14 had atypical cells and 1 had reactive cells. Positive uptake on FDG-PET was noted in 76 patients. The concordance of malignant histology and positive FDG-PET occurred in 58 of 76 patients (76%). Combining histologically confirmed MPE with atypical cytology, positive pleural FDG-PET uptake had a positive predictive value of 91% for MPE. An encasement pattern had a 100% PPV for malignancy. CONCLUSION: Positive FDG-PET pleural uptake represents an excellent method to identify MPE, especially in patients with an encasement pattern. This may eliminate the need for additional invasive procedures in some patients, even when initial pleural cytology is negative.

Design and methods of a randomized trial testing "Advancing care for COPD in people living with HIV by implementing evidence-based management through proactive E-consults (ACHIEVE)".

Chronic obstructive pulmonary disease (COPD) is one of the most common comorbid diseases among aging people with HIV (PWH) and is often mismanaged. To address this gap, we are conducting the study, "Advancing care for COPD in people living with HIV by Implementing Evidence-based management through proactive E-consults (ACHIEVE)." This intervention optimizes COPD management by promoting effective, evidence-based care and de-implementing inappropriate therapies for COPD in PWH receiving care at Veteran Affairs (VA) medical centers. Study pulmonologists are proactively supporting ID providers managing a population of PWH who have COPD, offering real-time evidence-based recommendations tailored to each patient. We are leveraging VA clinical and informatics infrastructures to communicate recommendations between the study team and clinical providers through the electronic health record (EHR) as an E-consult. If effective, ACHIEVE could serve as a model of effective, efficient COPD management among PWH receiving care in VA. This paper outlines the rationale and methodology of the ACHIEVE trial, one of a series of studies funded by the National Heart, Lung, and Blood Institute (NHLBI) within the ImPlementation REsearCh to DEvelop Interventions for People Living with HIV (PRECluDE) consortium to study chronic disease comorbidities in HIV populations.

Effect of Androgen Suppression on Clinical Outcomes in Hospitalized Men With COVID-19: The HITCH Randomized Clinical Trial.

Importance: SARS-CoV-2 entry requires the TMPRSS2 cell surface protease. Antiandrogen therapies reduce expression of TMPRSS2. Objective: To determine if temporary androgen suppression induced by degarelix improves clinical outcomes of inpatients hospitalized with COVID-19. Design, Setting, and Participants: The Hormonal Intervention for the Treatment in Veterans With COVID-19 Requiring Hospitalization (HITCH) phase 2, placebo-controlled, double-blind, randomized clinical trial compared efficacy of degarelix plus standard care vs placebo plus standard care on clinical outcomes in men hospitalized with COVID-19 but not requiring invasive mechanical ventilation. Inpatients were enrolled at 14 Department of Veterans Affairs hospitals from July 22, 2020, to April 8, 2021. Data were analyzed from August 9 to October 15, 2021. Interventions: Patients stratified by age, history of hypertension, and disease severity were centrally randomized 2:1 to degarelix, (1-time subcutaneous dose of 240 mg) or a saline placebo. Standard care included but was not limited to supplemental oxygen, antibiotics, vasopressor support, peritoneal dialysis or hemodialysis, intravenous fluids, remdesivir, convalescent plasma, and dexamethasone. Main Outcomes and Measures: The composite primary end point was mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at day 15 after randomization. Secondary end points were time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a temperature within reference range, maximum severity of COVID-19, and the composite end point at 30 days. Results: The trial was stopped for futility after the planned interim analysis, at which time there were 96 evaluable patients, including 62 patients randomized to the degarelix group and 34 patients in the placebo group, out of 198 initially planned. The median (range) age was 70.5 (48-85) years. Common comorbidities included chronic obstructive pulmonary disorder (15 patients [15.6%]), hypertension (75 patients [78.1%]), cardiovascular disease (27 patients [28.1%]), asthma (12 patients [12.5%]), diabetes (49 patients [51.0%]), and chronic respiratory failure requiring supplemental oxygen at baseline prior to COVID-19 (9 patients [9.4%]). For the primary end point, there was no significant difference between the degarelix and placebo groups (19 patients [30.6%] vs 9 patients [26.5%]; P = .67). Similarly, no differences were observed between degarelix and placebo groups in any secondary end points, including inpatient mortality (11 patients [17.7%] vs 6 patients [17.6%]) or all-cause mortality (11 patients [17.7%] vs 7 patents [20.6%]). There were no differences between degarelix and placebo groups in the overall rates of adverse events (13 patients [21.0%] vs 8 patients [23.5%) and serious adverse events (19 patients [30.6%] vs 13 patients [32.4%]), nor unexpected safety concerns. Conclusions and Relevance: In this randomized clinical trial of androgen suppression vs placebo and usual care for men hospitalized with COVID-19, degarelix did not result in amelioration of COVID-19 severity. Trial Registration: ClinicalTrials.gov Identifier: NCT04397718.

Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial.

BACKGROUND: Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity. METHODS: This is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3-5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated. DISCUSSION: In this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04397718. Registered on May 21, 2020.

The Natural History of a Patient With COVID-19 Pneumonia and Silent Hypoxemia.

A patient who declined all interventions, including oxygen, and recovered highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia.

The role of non-invasive ventilation in weaning and decannulating critically ill patients with tracheostomy: A narrative review of the literature.

INTRODUCTION: Invasive mechanical ventilation (IMV) is associated with several complications. Placement of a long-term airway (tracheostomy) is also associated with short and long-term risks for patients. Nevertheless, tracheostomies are placed to help reduce the duration of IMV, facilitate weaning and eventually undergo successful decannulation. METHODS: We performed a narrative review by searching PubMed, Embase and Medline databases to identify relevant citations using the search terms (with synonyms and closely related words) "non-invasive ventilation", "tracheostomy" and "weaning". We identified 13 publications comprising retrospective or prospective studies in which non-invasive ventilation (NIV) was one of the strategies used during weaning from IMV and/or tracheostomy decannulation. RESULTS: In some studies, patients with tracheostomies represented a subgroup of patients on IMV. Most of the studies involved patients with underlying cardiopulmonary comorbidities and conditions, and primarily involved specialized weaning centres. Not all studies provided data on decannulation, although those which did, report high success rates for weaning and decannulation when using NIV as an adjunct to weaning patient off ventilatory support. However, a significant percentage of patients still needed home NIV after discharge. CONCLUSIONS: The review supports a potential role for NIV in weaning patients with a tracheostomy either off the ventilator and/or with its decannulation. Additional research is needed to develop weaning protocols and better characterize the role of NIV during weaning.

Community-Acquired Pneumonia and Risk of Cardiovascular Events in People Living With HIV.

Background Hospitalization with community-acquired pneumonia (CAP) is associated with an increased risk of cardiovascular disease (CVD) events in patients uninfected with HIV. We evaluated whether people living with HIV (PLWH) have a higher risk of CVD or mortality than individuals uninfected with HIV following hospitalization with CAP. Methods and Results We analyzed data from the Veterans Aging Cohort Study on US veterans admitted with their first episode of CAP from April 2003 through December 2014. We used Cox regression analyses to determine whether HIV status was associated with incident CVD events and mortality from date of admission through 30 days after discharge (30-day mortality), adjusting for known CVD risk factors. We included 4384 patients (67% [n=2951] PLWH). PLWH admitted with CAP were younger, had less severe CAP, and had fewer CVD risk factors than patients with CAP who were uninfected with HIV. In multivariable-adjusted analyses, CVD risk was similar in PLWH compared with HIV-uninfected (hazard ratio [HR], 0.89; 95% CI, 0.70-1.12), but HIV infection was associated with higher mortality risk (HR, 1.49; 95% CI, 1.16-1.90). In models stratified by HIV status, CAP severity was significantly associated with incident CVD and 30-day mortality in PLWH and patients uninfected with HIV. Conclusions In this study, the risk of CVD events during or after hospitalization for CAP was similar in PLWH and patients uninfected with HIV, after adjusting for known CVD risk factors and CAP severity. HIV infection, however, was associated with increased 30-day mortality after CAP hospitalization in multivariable-adjusted models. PLWH should be included in future studies evaluating mechanisms and prevention of CVD events after CAP.

Underuse of Clinical Decision Rules and d-Dimer in Suspected Pulmonary Embolism: A Nationwide Survey of the Veterans Administration Healthcare System.

PURPOSE: The diagnosis of pulmonary embolism (PE) remains a challenge. CT pulmonary angiography (CTPA) for suspected PE has become the primary imaging modality, but concerns regarding overutilization, overdiagnosis, radiation, and costs have led to algorithms that combine a clinical decision rule (CDR) and highly sensitive d-dimer to identify patients in whom PE can be safely excluded without further studies. This has been identified as a top five Choosing Wisely recommendation in pulmonary medicine, but adherence is modest at best and actual utilization is unknown. Therefore, a survey was conducted to determine the prevalence of this approach in the Veterans Administration (VA) healthcare system. METHODS: A web-based questionnaire survey (SurveyGizmo.com) was developed and validated to query the utilization of CDR ± d-dimer in suspected PE. Key stakeholders identified from national VA mailing lists of radiology, pulmonary, and emergency medicine chiefs were sent an email describing the survey and provided a link for response. This study was reviewed and approved by our local institutional review board and accessing the link represented consent for participation. No personally identifiable data were collected and a drawing for a gift card was provided as an incentive. RESULTS: There were a total of 159 responses, with 120 fully completed surveys for analysis. The majority of respondents were chiefs (63%) with 11+ years of experience (80%), from hospitals with house staff (86%) and an emergency department (97%). Respondents were from emergency medicine (31%), pulmonary (27%), radiology (26%), and other departments (9%). The overwhelming majority of respondents (85%) did not require results of a CDR ± d-dimer before ordering a CTPA. Only 6.7% required a CDR + d-dimer, with others requiring either only a CDR (5.8%) or d-dimer (2.5%). The most common CDR was the Wells score, with only one using the Pulmonary Embolism Rule-Out Criteria. Nine of 18 (50%) regional Veterans Integrated Service Networks reported at least one site requiring a CDR before CTPA. An average of 9.6 CTPAs were estimated to be performed per week. Sorted by CDR and d-dimer use, 8 (CDR + d-dimer), 6.9 (CDR only), 8 (d-dimer only), 10.1 (no requirements) CTPA studies were performed weekly. The average CTPA yield for PE was estimated at 11.9% (CDR + d-dimer), 8% (CDR only), 2.5% (d-dimer only), and 7.6% (no requirements). CONCLUSIONS: The vast majority of hospitals within the VA system do not use a CDR ± d-dimer in the evaluation of patients with suspected PE. Utilization of a CDR and d-dimer may decrease CTPA utilization and increase yield, but this assessment is limited by the scope of the survey. CLINICAL IMPLICATIONS: CDR-guided strategies are recommended in the evaluation of suspected PE. Adherence within the VA healthcare system is very low. Further investigation is warranted to better characterize and improve the adherence to CDR-guided strategies and CTPA utilization.

Accuracy of electronic health record data for the diagnosis of chronic obstructive pulmonary disease in persons living with HIV and uninfected persons.

PURPOSE: No prior studies have addressed the performance of electronic health record (EHR) data to diagnose chronic obstructive pulmonary disease (COPD) in people living with HIV (PLWH), in whom COPD could be more likely to be underdiagnosed or misdiagnosed, given the higher frequency of respiratory symptoms and smoking compared with HIV-uninfected (uninfected) persons. METHODS: We determined whether EHR data could improve accuracy of ICD-9 codes to define COPD when compared with spirometry in PLWH vs uninfected, and quantified level of discrimination using the area under the receiver-operating curve (AUC). The development cohort consisted of 350 participants who completed research spirometry in the Examinations of HIV Associated Lung Emphysema (EXHALE) study, a pulmonary substudy of the Veterans Aging Cohort Study. Results were externally validated in 294 PLWH who performed spirometry for clinical indications from the University of Washington (UW) site of the Centers for AIDS Research Network of Integrated Clinical Systems cohort. RESULTS: ICD-9 codes performed similarly by HIV status, but alone were poor at discriminating cases from non-cases of COPD when compared with spirometry (AUC 0.633 in EXHALE; 0.651 in the UW cohort). However, algorithms that combined ICD-9 codes with other clinical variables available in the EHR-age, smoking, and COPD inhalers-improved discrimination and performed similarly in EXHALE (AUC 0.771) and UW (AUC 0.734). CONCLUSIONS: These data support that EHR data in combination with ICD-9 codes have moderately good accuracy to identify COPD when spirometry data are not available, and perform similarly in PLWH and uninfected individuals.

Medical Intensive Care Unit Admission Among Patients With and Without HIV, Hepatitis C Virus, and Alcohol-Related Diagnoses in the United States: A National, Retrospective Cohort Study, 1997-2014.

BACKGROUND: HIV, hepatitis C virus (HCV), and alcohol-related diagnoses (ARD) independently contribute increased risk of all-cause hospitalization. We sought to determine annual medical intensive care unit (MICU) admission rates and relative risk of MICU admission between 1997 and 2014 among people with and without HIV, HCV, and ARD, using data from the largest HIV and HCV care provider in the United States. SETTING: Veterans Health Administration. METHODS: Annual MICU admission rates were calculated among 155,550 patients in the Veterans Aging Cohort Study by HIV, HCV, and ARD status. Adjusted rate ratios and 95% confidence intervals (CIs) were estimated with Poisson regression. Significance of trends in age-adjusted admission rates were tested with generalized linear regression. Models were stratified by calendar period to identify shifts in MICU admission risk over time. RESULTS: Compared to HIV-/HCV-/ARD- patients, relative risk of MICU admission decreased among HIV-mono-infected patients from 61% (95% CI: 1.56 to 1.65) in 1997-2009% to 21% (95% CI: 1.16 to 1.27) in 2010-2014, increased among HCV-mono-infected patients from 22% (95% CI: 1.16 to 1.29) in 1997-2009% to 54% (95% CI: 1.43 to 1.67) in 2010-2014, and remained consistent among patients with ARD only at 46% (95% CI: 1.42 to 1.50). MICU admission rates decreased by 48% among HCV-uninfected patients (P-trend <0.0001) but did not change among HCV+ patients (P-trend = 0.34). CONCLUSION: HCV infection and ARD remain key contributors to MICU admission risk. The impact of each of these conditions could be mitigated with combination of treatment of HIV, HCV, and interventions targeting unhealthy alcohol use.

Electric Field-Induced Release and Measurement Liquid Biopsy for Noninvasive Early Lung Cancer Assessment.

Previously, we detected circulating tumor DNA that contained two EGFR mutations (p.L858R and exon19 del) in plasma of patients with late-stage non-small-cell lung carcinoma (NSCLC) using the electric field-induced release and measurement (EFIRM) platform. Our aim was to determine whether EFIRM technology can detect these mutations in patients with early-stage NSCLC. Prospectively, 248 patients with radiographically determined pulmonary nodules were recruited. Plasma was collected before biopsy and histologic examination of the nodule. Inclusion criteria were histologic diagnosis of benign nodule (control) and stage I or II adenocarcinoma harboring either p.L858R or exon19 delEGFR mutations. Plasma samples were available from 44 patients: 23 with biopsy-proven benign pulmonary nodules and 21 with stage I or II adenocarcinoma (12 p.L858R and 9 exon19 delEGFR variants). Samples were analyzed for the EGFR mutations using the EFIRM platform. Assay sensitivity was 92% for p.L858R (11 of 12 samples positive) and 77% for exon19 del (7 of 9 samples positive). Specificity was 91% with two false-positive results in 23 patients with EGFR-positive nodules and 95% for the entire 44-patient series. Concordance was 100% with identical mutations discovered in plasma and nodule biopsy. The EFIRM platform is able to noninvasively detect two EGFR mutations in individuals with early-stage NSCLC.

Tension hydropneumothorax as the initial presentation of Boerhaave syndrome.

Boerhaave syndrome, a rare yet frequently fatal diagnosis, is characterized by the spontaneous transmural rupture of the esophagus. The classic presentation of Boerhaave syndrome is characterized by Mackler's triad, consisting of chest pain, vomiting, and subcutaneous emphysema. However, Boerhaave syndrome rarely presents with all the features of Mackler's triad; instead, the common presentation of Boerhaave syndrome includes chest or epigastric pain, severe retching and vomiting, dyspnea, and shock. These symptoms are typically misdiagnosed as cardiogenic in origin. Due to its atypical presentation, rarity, and mimicry of emergent conditions, diagnosis of Boerhaave syndrome is often delayed, resulting in a high mortality rate at the time of diagnosis and with a subsequent exponential increase in mortality if treatment is delayed by greater than 48 hours. Here, we report two atypical presentations of Boerhaave syndrome presenting as tension hydropneumothorax and review ten previously reported cases of Boerhaave syndrome presenting as tension hydropneumothorax. This review serves to raise clinician awareness about the expansive and elusive ways by which esophageal perforation may present, and thereby facilitate timely and potentially life-saving diagnosis.

Non-invasive early detection of malignant pulmonary nodules by FISH-based sputum test.

BACKGROUND: Early detection decreases lung cancer mortality. The Target-FISH Lung Cancer Detection (LCD) Test is a non-invasive test designed to detect chromosomal changes (deletion or amplification) via Fluorescence in situ Hybridization (FISH) in sputum specimens from persons suspected of having lung cancer. We evaluated the performance of the LCD test in patients with highly suspicious pulmonary nodules who were scheduled for a biopsy procedure. METHODS: Induced sputum was collected from patients who were scheduled for biopsy of a solitary pulmonary nodule (0.8-3 cm) in one of 6 tertiary medical centers in the US and Israel. The lung cancer detection (LCD) Test combined sputum cytology and Target-FISH analysis on the same target cells and the results were compared to the pathology. Participants with non-surgical negative biopsy results were followed for 2 years to determine their final diagnosis. RESULTS: Of the 173 participants who were evaluated, 112 were available for analysis. Overall, the LCD test had a sensitivity of 85.5% (95% CI, 76.1-92.3), specificity of 69% (95% CI, 49.2-84.7) and an accuracy of 81.3% (95% CI, 72.8-88). The positive and negative predictive values (PPV, NPV) were 88.8% and 62.5%, respectively. The LCD test was positive in 9 of 11 lung cancer patients who had an initial negative biopsy. CONCLUSIONS: In a cohort of patients with highly suspicious lung nodules, the LCD test is a non-invasive option with good sensitivity and a high positive predictive value. A positive LCD test reinforces the need to aggressively pursue a definitive diagnosis of suspicious nodules.